The long-term objective of the research proposed here is to set the stage for the discovery of a new class of orally bioavailable, small-molecule drugs that target the PD-1 protein for the treatment of patients with Alzheimer?s Disease (AD) or mild cognitive impairment (MCI). Inhibition of PD-1 in mice by anti-PD-1 monoclonal antibodies (mAbs) has been shown to lead to the recruitment of monocyte-derived macrophages in the brain, clearance of cerebral amyloid-b plaques, and improved cognitive performance. Peripheral blood mononuclear cells (PBMCs) from patients with AD or MCI, or age-matched healthy controls support a role of the PD-1/PD-L1 pathway in the neuroinflammation associated with AD. PD-1 inhibitors have had a dramatic impact in oncology as a member of a new class of drugs called immune checkpoint inhibitors. These drugs, however, can have serious side effects including a life-threatening runaway immune response, termed a cytokine storm. When they occur, these side effects are difficult to manage, especially since all current PD-1 inhibitors are monoclonal antibodies (mAbs) that have long half-lives in patients (typically several weeks) making timely drug removal nearly impossible. Small-molecule anti-PD-1 drugs would offer safety advantages due to their shorter half-lives (typically dosed once or twice daily). This is particularly important in elderly patients with AD or MCI. Identifying small-molecules that bind to PD-1 and disrupt the interaction of PD-1 with its ligands (PD-L1 and PD-L2) has proven to be very difficult. The research proposed in this supplement will use one of the key strategies from the parent Avant Garde award for the HIV-1 gp41 target but apply it to PD-1. Specifically, we aim to use scFv fragments against the CC? loop and/or the FG loop to stabilize a conformation of PD-1 that presents an exposed pocket suitable for small-molecule drug discovery. If successful, this work could set the stage for the discovery of anti-PD-1 drugs that could have utility for the treatment of AD. Importantly, the learnings from work with each of these drug targets are likely to help the efforts with the other.